Oncotarget

Research Papers:

Synergistic targeting of Sp1, a critical transcription factor for myeloma cell growth and survival, by panobinostat and proteasome inhibitors

Ariunzaya Bat-Erdene, Hirokazu Miki, Asuko Oda, Shingen Nakamura, Jumpei Teramachi, Ryota Amachi, Hirofumi Tenshin, Masahiro Hiasa, Masami Iwasa, Takeshi Harada, Shiro Fujii, Kimiko Sogabe, Kumiko Kagawa, Sumiko Yoshida, Itsuro Endo, Kenichi Aihara and Masahiro Abe _

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Oncotarget. 2016; 7:79064-79075. https://doi.org/10.18632/oncotarget.12594

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Abstract

Ariunzaya Bat-Erdene1, Hirokazu Miki2, Asuko Oda1, Shingen Nakamura1, Jumpei Teramachi1,4, Ryota Amachi1,3, Hirofumi Tenshin1,3, Masahiro Hiasa1,3, Masami Iwasa1, Takeshi Harada1, Shiro Fujii1, Kimiko Sogabe1, Kumiko Kagawa1, Sumiko Yoshida1, Itsuro Endo1, Kenichi Aihara1, Masahiro Abe1

1Department of Hematology, Endocrinology and Metabolism, Institute of Biomedical Sciences, Tokushima University Graduate School of Medicine, Tokushima, Japan

2Division of Transfusion Medicine and Cell Therapy, Tokushima University Hospital, Tokushima, Japan

3Department of Orthodontics and Dentofacial Orthopedics, Tokushima University Graduate School of Oral Sciences, Tokushima, Japan

4Department of Histology and Oral Histology, Tokushima University Graduate School of Oral Sciences, Tokushima, Japan

Correspondence to:

Masahiro Abe, email: masabe@tokushima-u.ac.jp

Keywords: multiple myeloma, panobinostat, proteasome inhibitors, caspase-8, Sp1

Received: July 16, 2016     Accepted: September 29, 2016     Published: October 12, 2016

ABSTRACT

Panobinostat, a pan-deacetylase inhibitor, synergistically elicits cytotoxic activity against myeloma (MM) cells in combination with the proteasome inhibitor bortezomib. Because precise mechanisms for panobinostat’s anti-MM action still remain elusive, we aimed to clarify the mechanisms of anti-MM effects of panobinostat and its synergism with proteasome inhibitors. Although the transcription factor Sp1 was overexpressed in MM cells, the Sp1 inhibitor terameprocol induced MM cell death in parallel with reduction of IRF4 and cMyc. Panobinostat induced activation of caspase-8, which was inversely correlated with reduction of Sp1 protein levels in MM cells. The panobinostat-mediated effects were further potentiated to effectively induce MM cell death in combination with bortezomib or carfilzomib even at suboptimal concentrations as a single agent. Addition of the caspase-8 inhibitor z-IETD-FMK abolished the Sp1 reduction not only by panobinostat alone but also by its combination with bortezomib, suggesting caspase-8-mediated Sp1 degradation. The synergistic Sp1 reduction markedly suppressed Sp1-driven prosurvival factors, IRF4 and cMyc. Besides, the combinatory treatment reduced HDAC1, another Sp1 target, in MM cells, which may potentiate HDAC inhibition. Collectively, caspase-8-mediated post-translational Sp1 degradation appears to be among major mechanisms for synergistic anti-MM effects of panobinostat and proteasome inhibitors in combination.


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